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Enzyme Inhibitor

Ceralasertib + Trastuzumab Deruxtecan for Solid Tumors

Phase 1

Recruiting

Led By Kanwal P Raghav

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

Age >= 18 years

Must not have

Any previous treatment with an ATR inhibitor

Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Awards & highlights

No Placebo-Only Group

Summary

This trial will find the best dose and safety of ceralasertib when given with trastuzumab deruxtecan to treat patients with solid tumors that have a change in the HER2 gene or protein.

Who is the study for?

Adults with advanced solid tumors expressing HER2, who've tried at least one chemotherapy, can join this trial. They must have a measurable tumor and be able to undergo biopsies. Key health requirements include proper liver and kidney function, controlled HIV if present, no severe heart issues or lung disease like ILD/pneumonitis, and not pregnant.

What is being tested?

The DASH trial is testing the combination of two drugs: DS-8201a (trastuzumab deruxtecan) which targets HER2 cancer cells with attached chemo drug deruxtecan; and AZD6738 (ceralasertib), which may halt tumor growth by blocking certain enzymes. The study has two phases to determine safety and compare responses in colorectal/gastroesophageal cancers.

What are the potential side effects?

Potential side effects include reactions related to immune system activation such as inflammation in organs or infusion-related symptoms. There might also be typical chemotherapy side effects like fatigue, nausea, blood cell count changes increasing infection risk, and potential heart or lung complications.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am fully active or restricted in physically strenuous activity but can do light work.

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I am 18 years old or older.

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My disease cannot be removed by surgery and has spread.

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I have a tumor that can be measured on a CT scan.

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I have an advanced solid tumor, such as breast or colon cancer.

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I agree to a biopsy of my cancer that can be easily reached.

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My tumor is HER2-positive, confirmed by a certified lab.

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My heart pumps well, with an ejection fraction of 50% or higher.

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My cancer is confirmed to be advanced stomach, esophagus, or colorectal.

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I've had chemotherapy for advanced cancer but it didn't work or I couldn't tolerate it.

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I am not pregnant.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have never been treated with an ATR inhibitor.

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I cannot take pills by mouth or have stomach issues that affect medication absorption.

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I haven't had a heart attack in the last 6 months and my heart functions well.

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I have spinal cord compression or active brain metastases.

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I have lung problems due to another illness.

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I am not taking strong CYP3A inhibitors.

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I need treatment to remove fluid from my chest, abdomen, or around my heart.

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I have taken corticosteroids within the last 2 weeks.

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I do not have any unmanaged ongoing illnesses.

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I am not taking chloroquine or hydroxychloroquine.

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I have high blood pressure that needs treatment.

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I have had a bone marrow or double umbilical cord blood transplant.

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I experience significant drops in blood pressure when standing.

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I have been diagnosed with MDS/AML or show signs of these conditions.

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I do not have an infection that needs IV treatment.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Differential pharmacodynamic (PD) profile of tumor tissue (DNA damage & repair) (Dose expansion phase)

Incidence of adverse events (Dose escalation phase)

Recommended phase 2 dose (Dose escalation phase)

Secondary study objectives

Anti-tumor activity of DS-8201a plus (+) AZD6738

Objective response rate (ORR)

PD markers

Other study objectives

Association of HER2 expression level and HER2 gene copy number and ORR

Palladium

Association of TOP1 expression level and ORR

+2 more

Side effects data

From 2024 Phase 2 trial • 95 Patients • NCT04989816

77%

Anaemia

73%

White blood cell count decreased

61%

Neutrophil count decreased

53%

Platelet count decreased

43%

Nausea

40%

Decreased appetite

39%

Hypoalbuminaemia

32%

Aspartate aminotransferase increased

32%

Vomiting

28%

Weight decreased

26%

Hypokalaemia

25%

Asthenia

25%

Alanine aminotransferase increased

24%

Hypocalcaemia

22%

Hyponatraemia

19%

Constipation

19%

Fatigue

17%

Lymphocyte count decreased

15%

Diarrhoea

13%

Covid-19

12%

Blood alkaline phosphatase increased

12%

Blood bilirubin increased

12%

Gamma-glutamyltransferase increased

Hyperuricaemia

Pyrexia

Dizziness

Hyperglycaemia

Abdominal distension

Oedema peripheral

Insomnia

Thrombocytopenia

Bilirubin conjugated increased

Blood creatinine increased

White blood cell count increased

Hypochloraemia

Abdominal pain

Dyspepsia

Hypoaesthesia

Coronavirus infection

Cough

Pneumonia

Hepatic function abnormal

Amylase increased

Blood lactate dehydrogenase increased

Ejection fraction decreased

Hypoproteinaemia

Back pain

Mouth ulceration

Interstitial lung disease

Productive cough

Covid-19 pneumonia

Gastrointestinal haemorrhage

Febrile neutropenia

Death

Cerebral infarction

Myelosuppression

Haemorrhage intracranial

Dysphagia

Jaundice cholestatic

Gastrointestinal infection

Malnutrition

Mental disorder

Haematuria

Renal failure

Pulmonary embolism

Deep vein thrombosis

Arrhythmia

Sepsis

Upper gastrointestinal haemorrhage

100%

80%

60%

40%

20%

Study treatment Arm

T-DXd

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (trastuzumab deruxtecan, ceralasertib)Experimental Treatment8 Interventions

Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 and ceralasertib PO BID on days 1-7. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: During the dose-expansion phase, the first 6 patients in each disease cohort (gastroesophageal cancer \[cohort A\] and colorectal cancer \[cohort B\]) receive only trastuzumab deruxtecan for the first cycle, followed by trastuzumab deruxtecan and ceralasertib together in subsequent cycles. Additionally, patients undergo tissue biopsy on study and blood sample collection, CT or PET/CT and ECHO or MUGA throughout the study.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Biopsy

2014

Completed Phase 4

~1150

Biospecimen Collection

2004

Completed Phase 3

~2030